Research Article Clinical Profile of Dengue Fever in Children...

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Research Article Clinical Profile of Dengue Fever in Children: A Study from Southern Odisha, India Shubhankar Mishra, Ramya Ramanathan, and Sunil Kumar Agarwalla Department of Paediatrics, MKCG Medical College, Berhampur, Odisha 760004, India Correspondence should be addressed to Shubhankar Mishra; [email protected] Received 31 December 2015; Revised 16 March 2016; Accepted 5 April 2016 Academic Editor: Nobuhiro Ohkohchi Copyright © 2016 Shubhankar Mishra et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. In India, dengue epidemics are becoming more frequent (WHO, 2008). e majority of dengue viral infections are self-limiting, but complications may cause high morbidity and mortality. Objectives. To assess the clinical profile of the dengue infection in children less than 14 years of age and to evaluate the outcomes of dengue fever from September 2013 to August 2015 at the Pediatric Department of Maharaja Krishna Chandra Gajapati Medical College, the largest tertiary care hospital of southern Odisha. Results. A total of 97 cases were classified into 84 (86.59%) nonsevere and 13 (13.40%) severe dengue cases. e most common age of presentation was above 11 yrs. e mean age of admission was 8.7 yrs. e most common presenting symptom was fever seen in 100% and hepatomegaly (43.8%), the most common physical finding. Gastrointestinal bleeding was markedly seen in severe dengue (76.9%). Elevation in aspartate transaminase (SGOT) was found in 47.42% and thrombocytopenia in 27.5%. e correlation between hepatomegaly and elevated SGOT was significant ( value 0.0346). Case fatality rate (CFR) was 1.03%. e mean duration of hospitalisation was 3.8 days. Conclusion. In children, if symptoms like fever, pain, rashes, and vomiting are associated with hepatomegaly and elevated SGOT in context of low TPC, a strong possibility of dengue fever is present, especially in an epidemic setting. Early suspicion and effective management can reduce the severity. 1. Introduction Globally 50 million dengue infections are reported annually [1]. e first dengue fever in India was reported during 1956 from Vellore and the first dengue haemorrhagic fever occurred in Calcutta in 1963 [2]. In India the annual incidence is estimated to be 7.5 to 32.5 million [3]. In Odisha, a state of Eastern India, the first outbreak was reported in 2010, followed by extensive outbreaks in 2011, affecting a large number of people. According to the WHO the case fatality rate for dengue is roughly 5% [1]. Aedes albopictus was found to be the most abundant vector in the areas sur- veyed, followed by Aedes aegypti. DENV-2 is the prevailing serotype [4]. e case fatality rate in patients with severe dengue infection which consists of dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) can be as high as 44% [2, 5]. If intervention occurs early, mortality is less than 1% [6]. Dengue fever presents as common viral fever which causes dangerous complications. Dengue reinfection is observed to be more severe in children due to immunological phenomenon [7]. In 2010, 25 cases and five deaths were reported from Odisha [8]. Rapid increase in the dengue cases in 2012 became a public health concern in Eastern India as the majority of cases were affecting the young adolescents. e objective of this study was to assess the clinical profile of the dengue infection in children less than 14 years of age and to evaluate the outcome of dengue fever in the southeastern part of India where dengue outbreaks are rampant. 2. Material and Methods It was a prospective observational study. All probable cases that had high grade fever, lymphadenopathy, hepatomegaly, features of shock or haemorrhage, and so forth and were admitted with provisional diagnosis of dengue fever to the Paediatric Ward of Maharaja Krishna Chandra Gajapati Med- ical College, Berhampur, Odisha, were taken into account. All children aged up to 14 years with positive dengue tests, Hindawi Publishing Corporation Scientifica Volume 2016, Article ID 6391594, 6 pages http://dx.doi.org/10.1155/2016/6391594

Transcript of Research Article Clinical Profile of Dengue Fever in Children...

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Research ArticleClinical Profile of Dengue Fever in Children: A Study fromSouthern Odisha, India

Shubhankar Mishra, Ramya Ramanathan, and Sunil Kumar Agarwalla

Department of Paediatrics, MKCGMedical College, Berhampur, Odisha 760004, India

Correspondence should be addressed to Shubhankar Mishra; [email protected]

Received 31 December 2015; Revised 16 March 2016; Accepted 5 April 2016

Academic Editor: Nobuhiro Ohkohchi

Copyright © 2016 Shubhankar Mishra et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Background. In India, dengue epidemics are becoming more frequent (WHO, 2008). The majority of dengue viral infections areself-limiting, but complications may cause high morbidity and mortality. Objectives. To assess the clinical profile of the dengueinfection in children less than 14 years of age and to evaluate the outcomes of dengue fever from September 2013 to August 2015at the Pediatric Department of Maharaja Krishna Chandra Gajapati Medical College, the largest tertiary care hospital of southernOdisha. Results. A total of 97 cases were classified into 84 (86.59%) nonsevere and 13 (13.40%) severe dengue cases. The mostcommon age of presentation was above 11 yrs. The mean age of admission was 8.7 yrs. The most common presenting symptomwas fever seen in 100% and hepatomegaly (43.8%), the most common physical finding. Gastrointestinal bleeding was markedlyseen in severe dengue (76.9%). Elevation in aspartate transaminase (SGOT) was found in 47.42% and thrombocytopenia in 27.5%.The correlation between hepatomegaly and elevated SGOT was significant (𝑃 value 0.0346). Case fatality rate (CFR) was 1.03%.The mean duration of hospitalisation was 3.8 days. Conclusion. In children, if symptoms like fever, pain, rashes, and vomiting areassociated with hepatomegaly and elevated SGOT in context of low TPC, a strong possibility of dengue fever is present, especiallyin an epidemic setting. Early suspicion and effective management can reduce the severity.

1. Introduction

Globally 50 million dengue infections are reported annually[1]. The first dengue fever in India was reported during1956 from Vellore and the first dengue haemorrhagic feveroccurred inCalcutta in 1963 [2]. In India the annual incidenceis estimated to be 7.5 to 32.5 million [3]. In Odisha, astate of Eastern India, the first outbreak was reported in2010, followed by extensive outbreaks in 2011, affecting alarge number of people. According to the WHO the casefatality rate for dengue is roughly 5% [1]. Aedes albopictuswas found to be the most abundant vector in the areas sur-veyed, followed by Aedes aegypti. DENV-2 is the prevailingserotype [4]. The case fatality rate in patients with severedengue infection which consists of dengue haemorrhagicfever (DHF) and dengue shock syndrome (DSS) can be ashigh as 44% [2, 5]. If intervention occurs early, mortality isless than 1% [6]. Dengue fever presents as common viral feverwhich causes dangerous complications. Dengue reinfection is

observed to bemore severe in children due to immunologicalphenomenon [7]. In 2010, 25 cases and five deaths werereported fromOdisha [8]. Rapid increase in the dengue casesin 2012 became a public health concern in Eastern India as themajority of cases were affecting the young adolescents. Theobjective of this study was to assess the clinical profile of thedengue infection in children less than 14 years of age and toevaluate the outcome of dengue fever in the southeastern partof India where dengue outbreaks are rampant.

2. Material and Methods

It was a prospective observational study. All probable casesthat had high grade fever, lymphadenopathy, hepatomegaly,features of shock or haemorrhage, and so forth and wereadmitted with provisional diagnosis of dengue fever to thePaediatricWard ofMaharaja KrishnaChandraGajapatiMed-ical College, Berhampur, Odisha, were taken into account.All children aged up to 14 years with positive dengue tests,

Hindawi Publishing CorporationScientificaVolume 2016, Article ID 6391594, 6 pageshttp://dx.doi.org/10.1155/2016/6391594

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Table 1: Epidemiology.

Parameter Variables Numbers % Nonseveredengue Severe dengue Stats

Age

<3 yrs 15 15.4% 15 0Mean age8.7 yrs

4–7 yrs 22 22.6% 21 18–11 yrs 27 27.8% 24 3>11 yrs 33 34% 24 9

Sex Male 75 77.3% 66 9Female 22 22.7% 18 4

Duration ofhospitalisation

0–3 days 28 28.8% 27 1Mean duration

3.8 days3–6 days 62 63.9% 57 5>6 days 7 7.2% 0 7

Day of admission0–3 days 41 42.2% 38 3

Mean day3.4 days3–6 days 51 52.5% 43 8

>6 days 5 5.1% 3 2

ClassificationUndifferentiated fever 31 31.9%

DF (with and without warning signs) 53 54.6%Severe dengue fever (DHF) 13 13.4%

either NS1 antigen, IgM, IgG antibody rapid serologicaltest kit (J. Mitra and Co. Pvt. Ltd.), or ELISA, were takeninto the study group. As the duration of history of fevermight be fallacious the patients were subjected to all threeserological tests. Children who were positive for malaria,meningitis, and enteric fever were excluded from the study.The whole number of patients included in our study was 97(𝑛 = 97). Cases were followed up daily for the clinical andlaboratory parameters. Blood parameters were monitoredevery day till remarkable improvement seen clinically andhaematologically. Averages of TLC, TPC, Hb, haematocrit,and so forth were calculated for each patient and recorded.Daily vitals weremonitoredwith tourniquet test. Chest X-ray,ultrasonography, and liver function tests were done on day3 of admission on all the patients. The patients were treatedwith oral paracetamol, intravenous fluids, blood products,and inotropes as per the recent WHO dengue guidelines[2]. The frequency of various signs and symptoms and thelaboratory tests were compared between the nonsevere andsevere disease. The results were tabulated and correlated.Theoutcomes were recorded.

The clinical manifestations and laboratory findings likehaemoglobin estimation, total platelet count, haematocritestimation, NS1 antigen, and IgM antibody of each groupof illness were compared using Fisher’s exact test for pro-portions. GraphPad version 6.0. software and SPSS version22.0.0.0 software were used for data entry and analysis. 𝑃value below 0.05 was considered significant. Written consentwas taken from the parents before enrolling in the study. Eth-ical committee clearance was taken from Maharaja KrishnaChandra Gajapati Medical College before starting this study.

3. Observations and Results

Thetotal number of caseswas 97, out ofwhich 84were cases ofnonsevere dengue (undifferentiated fever, dengue fever with

warning signs, and dengue fever without warning signs) and13 were cases of severe dengue (DHF and DSS) according toWHO guidelines [2]. There were 75 (77.31%) males and 22(22.68%) females in our study. Both the groups of severe andnonsevere dengue males had high incidence. The male-to-female ratio was 3.4 : 1. The maximum number of cases, 33(34.02%), was seen in the group above 11 years of age, out ofwhom male children were 25 (33.33%) and female children 8(36.36%). The mean age of hospitalised patients was 8.7 yrs.63.9% of patients were admitted in the hospital for 3–6 days.Seven children out of 13 severe dengue patients were admittedfor more than 6 days. The mean tenure of hospitalisation was3.8 days. In severe dengue cohort the mean stay was 5.8 days.The mean delay in admission after appearance of fever was3.4 days (Table 1).The total admissions for diagnosed cases ofdengue in adults were 211 in our hospital in the duration oftime of our study.

The majority of the cases were admitted in the rainy andwinter season between themonths of July andNovember.Thepeak of admission was seen in the month of September with59 cases (60.8%).The least admissionwas seen in the summerseason, specifically in themonth ofApril, consisting of 4 cases(4.1%).

Fever was present in 100% of the cases; myalgia (76.8%)and abdominal pain (54.3%) were common. Hepatomegaly(43.8%) was the most common physical finding. The mostcommon bleeding manifestations in both severe and nonse-vere dengue were petechiae (22.1%). Gastrointestinal bleed-ing was significantly seen in severe dengue cases. 58.76%of the cases had normal leukocyte count, while leucopoeniawas seen in 25.77% and leukocytosis in 15.46% of the cases.Among the liver enzymes, SGOT was elevated in a largerproportion (47.42%) of patients when compared to alanineaminotransferase (SGPT) which was 30.92%. Elevation inSGOT was significantly seen in those with severe dengue(76.92%, 𝑃 value: 0.0346) rather than nonsevere dengue

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(42.85%). SGPT was very high (>1000 IU/L) in 3 patientswhereas SGOT was very high (>1000 IU/L) in 5 patients. Allthese patients with high liver enzymes had other severitiesalso. Out of them one child that had very high titre of bothliver enzymes succumbed despite admission to the intensivecare unit. Parameters like prothrombin time (PT) and acti-vated partial thromboplastin time (aPTT) were abnormal in23 (23.7%) patients. In 10 (76.9%) cases of severe denguePT/aPTT levels came out to be abnormal. 27.83% presentedwith thrombocytopenia (platelet < 100000). 69.23% of severedengue cases had thrombocytopenia whereas only 21.42% ofnonsevere dengue cases had thrombocytopenia.Thrombocy-topenia was seen to be more relevant in those with severedengue. One of the important findings of dengue is raisedhaematocrit which was seen in 34.02% of the cases and it wasstatistically not significant.

25.77% of the cases were detected to have pleural effusionby chest X-ray (PA view and oblique view in right lateraldecubitus). Right sided effusion (15.46%) was most com-monly seen followed by bilateral effusion (6.18%). Amongthe severe dengue cases, the majority, 38.46%, presented withbilateral effusion. Ultrasound of the abdomen detected hep-atomegaly in 52.75% of the cases, which is the most commonfinding followed by ascites (25.77%) and gall bladder walledema (2.06%).

In our study, the majority of the patients were positivefor NS1 followed by IgM (Table 2) as a large number ofpatients presented within 4 days of fever. Serum IgG wasestimated in those children who presented with history of 7days. Tourniquet test was found to be negative in themajorityof the patients. In this study it was found that the bleedingmanifestation had no correlation with thrombocytopenia,hepatomegaly, and raised SGOT (Table 3). All 97 patients hadfever and they were treated with antipyretics (paracetamol)in appropriate doses. Patients who presented with warningsigns and stable vital signs were initially encouraged to takeoral fluids; if they were not tolerated intravenous fluidswere started according to the WHO guidelines. Among 97patients, 27.83% of the cases needed intravenous fluids andthe majority were severe dengue cases (76.92%). Dopaminewas required in 4.12% of the cases and all of themwere severedengue cases (30.76%). Adrenaline was used only in onepatient who belonged to the severe dengue category. Plateletconcentrate was given for 4 severe dengue cases. Whole freshblood transfusion was needed in 4.12% of the cases and all ofthem were severe dengue cases (Table 4). In our study all 84(86.59%) of nonsevere dengue cases recovered. Among thesevere dengue cases, 13 (13.40%), 12 cases (12.37%) recoveredand 1 case (1.03%) expired due to intractable shock.

4. Discussion

Dengue is an important arboviral infection in tropicalcountries. Global incidence of dengue fever has increaseddramatically in the recent decades [6]. There are very fewstudies based on the revised new dengue classification.

Based on the WHO TDR 2009 dengue guidelines, in ourstudy, the total number of cases analysed was 97, out of which84 (86.59%) were categorised as cases of nonsevere dengue

which included both undifferentiated fever and dengue fever(DF) (both with and without warning signs) and 13 (13.40%)were cases of severe dengue (DHF grades 1–4).Themaximumnumbers of cases were seen in the group >11 years of age(34.02%) and the least affected age group was infants. Moreinvolvement in adolescent children can be explained bydiurnal adaptation of Aedes mosquito in stored water. Thesechildren work in open field. This makes them prone torepeated attacks by Aedes mosquitoes. There was significantdifference in male : female ratio in our study (3.4 : 1) whereasin other studies there were no such significant differences [9].This was probably due to more importance being given to themale children in the Indian society. Covered dress used byfemales may be another cause for fewer incidences. Increasedadmissions in the rainy and winter seasons can be explainedby breeding season ofmosquitoes which is similar to previousstudies [10]. Duration of hospitalisation was more in case ofsevere dengue patients. But delay in hospitalisation did notpredict the severity in our study.

In our study fever was present in all cases. Abdominalpain, vomiting, retroorbital pain, and abdominal distensionwere seen commonly. This goes with previous study [10].Bleeding in dengue is multifactorial. The most commonbleedingmanifestations in both severe and nonsevere denguewere petechiae, purpura, and ecchymosis. Gastrointestinalbleeding was significantly seen in severe dengue cases. Hae-matemesis was the most common bleeding manifestationreported in other Indian studies. Convulsion due to infectionis very rare. Two patients in the severe dengue grouphad convulsion after having DSS. There was no correlationbetween platelet counts and bleeding manifestations in ourstudy. A similar finding was also noted in other studies[11]. Various factors apart from thrombocytopenia lead tobleeding in dengue. They are decreased platelet function,fibrinogen consumption, prolongation of PT/PTT, and vas-culopathy [12]. In our study, in the majority of the patientstourniquet test was found to be negative, whereas studies inother countries, especially Southeast Asian countries, reporttourniquet test positivity as the commonest bleeding mani-festation [13]. Low proportion of positive tourniquet test inIndian studies may be due to the darker skin colour in Indianchildren [14]. The most consistent finding was hepatomegaly,which was similar to many other studies [10, 11]. Amongthe various clinical findings hypotension, pleural effusion,and respiratory distress were notable and were analogousto other studies. Leukopenia was seen, which was similarto two other studies [10, 14]. The earliest haematologicalabnormality is a progressive decline in total WBC countin patients of dengue [2]. Leukopenia was not significantlyrelated with severe dengue cases which were against someresults [15]. In our study thrombocytopenia was seen to bemore in those with severe dengue [15]. There were a lowproportion of children with evidence of haemoconcentrationin our study group. The percentage increase in haematocritis an accurate indicator of vascular permeability and plasmaleakage. But it was also reported in previous studies thatin some cases the fluid leakage does not achieve a highdegree haemoconcentration even if the patient is in shock;this explains our findings. In some DF patients the rise of

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Table 2: Investigation.

Investigations Variations Nonsevere dengue(𝑛 = 84)

Severe dengue(𝑛 = 13)

Total(𝑛 = 97) 𝑃 value

TLC

Leukopenia (<4000 cells/mm3) 22 (26.19%) 3 (23.07%) 25(25.77%)

Leukocytosis (>11000 cells/mm3) 13 (15.47%) 2 (15.38%) 15(15.46%)

Normal TLC (4000–11000/mm3) 49 (58.33%) 8 (61.53%) 57(58.7%)

Liver enzymes

Rise in SGPT (IU/L)

Total 25 (29.76%) 5 (38.46%) 30(30.92%) 0.5326

50–200U 23 1200–1000U 2 1>1000U 0 3

Rise in SGOT (IU/L)

Total 36 (42.85%) 10 (76.92%) 46(47.42%) 0.0346∗

50–200U 31 1200–1000U 5 4>1000U 0 5

TPC

>100001 66 (78.57%) 4 (30.76%) 70(72.16%)

100000–50001 12 (14.28%) 4 (30.76%) 16(16.49%)

<50000 6 (7.14%) 5 (38.46%) 11(11.34%)

Haematocrit>36.3% 27 (32.14%) 6 (46.15%) 33

(34.02%)

<36.3% 57 (67.85%) 7 (53.84%) 64(65.97%)

Chest X-ray

Pleural effusion 17 (20.23%) 8 (61.53%) 25(25.77%) 0.0037∗

Right sided effusion 12 (14.28%) 3 (23.07%) 15(15.46%) 0.4179

Left sided effusion 4 (4.76%) 0 4 (4.12%)Right + left effusion 1 (1.19%) 5 (38.46%) 6 (6.18%) 0.0001∗

USG of abdomen

Hepatomegaly 41 (48.80%) 10 (76.92%) 51(52.57%)

Ascites 19 (22.61%) 6 (46.15%) 25(25.77%)

Gall bladder wall edema 0 2 (15.38%) 2 (2.06%)

Dengue serology

NS1 43 (51.19%) 3 (23.07%) 46(47.42%)

IgM 30 (35.71%) 2 (15.38%) 32(32.98%)

IgG 3 (3.57%) 0 3 (3.09%)

IgM & IgG 5 (5.95%) 6 (46.15%) 11(11.30%)

NS1 & IgM 3 (3.57%) 2 (15.38%) 5 (5.14%)∗Significant 𝑃 value.

PCV could have been due to dehydration as a result of poorintake and vomiting [16]. There are no clear-cut guidelinesfor haemoconcentration in the Indian population. Elevationof SGOT was significantly more compared to SGPT in thepresent study and ismore associatedwith severity of infectionwhich coincides with others also [14]. SGOT raise more than

SGPT in dengue may be due to involvement of myocytes.Value more than 1000 IU/L is seen in severe dengue. Veryhigh levels of SGOT and SGPT indicate severity of the diseasealong with morbidity and mortality. This differs from thepattern seen in viral hepatitis [17]. In this study one child whohad liver enzymes >1000 IU/L succumbed on the second day

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Table 3: Hepatic manifestations.

Bleeding manifestations𝑃 value

Present Absent TotalThrombocytopenia 0.3314

Present 11 16 27Absent 20 50 70Total 31 66 97

Hepatomegaly 0.2784Present 17 26 43Absent 15 39 54Total 32 65 97

Raised SGOT 0.2808Present 18 28 46Absent 14 37 51Total 32 65 97

Table 4: Management.

ManagementNonseveredengue(𝑛 = 84)

Severedengue(𝑛 = 13)

Total(𝑛 = 97)

Antipyretics 84 13 97

Intravenous fluids 17(20.23%)

10(76.92%)

27(27.83%)

Platelet transfusion 0 4 (30.76%) 4 (4.12%)Whole fresh blood transfusion 0 4 (30.76%) 4 (4.12%)Dopamine 0 4 (30.76%) 4 (4.12%)Adrenaline 0 1 (7.69%) 1 (1.03%)

of hospitalisation in spite of all measures. Rise in PT/aPTTalso depicts severity of disease. Ascites and pleural effusionwere common presentations, whereas chest X-ray revealedpleural effusion in 25.77%. In USG of the abdomen rightsided effusion (15.46%) was most commonly seen whichwas similar to the previous study [11]. Pleural effusion ismore significant in severe dengue. Among types of effusionsbilateral pleural effusion is more indicative of severity of thedisease. In our study all nonsevere dengue cases recovered.Among the severe dengue cases 12 cases recovered and 1 childexpired due to intractable shock.

There was less mortality in the present study group,whereas mortality rate was high in earlier previous studies.This could be due to delay in recognition of epidemic inprevious years or delay in seeking medical attention. Casefatality rate (CFR) of the SEAR countries in 2006 was lessthan 1%. India, Indonesia, Bhutan, and Nepal still have casefatality rates above 1% [18]. Early diagnosis and improved casemanagement of dengue fever are required to bring downCFRto below 1%.

5. Conclusion

Dengue is a common disease in this part of the world. Itis one of the dreaded fevers for the paediatric age group.The disease has various presentations and features, but early

diagnosis and management can decrease case fertility ratesignificantly. In our study we have enlisted all the typical andatypical presentations, epidemiological data, investigations,and management according to recent WHO guidelines.Severe dengue is very dangerous for children. Lab parameterlike raised SGOT is very significant for distinguishing severedisease fromnonsevere variety. Pleural effusion is a dominantfeature of severe disease. This study will elaborate knowledgeabout the disease and will improve the outcome.

Abbreviations

SGOT: Aspartate transaminaseCFR: Case fatality rateWHO: World Health OrganizationDHF: Dengue haemorrhagic feverDSS: Dengue shock syndromeIgM antibody: Immunoglobulin M antibodyIgG antibody: Immunoglobulin G antibodyTLC: Total leukocyte countTPC: Total platelet countHb: HaemoglobinSGPT: Alanine aminotransferaseaPTT: Activated partial thromboplastin timePT: Prothrombin timeDF: Dengue feverPCV: Packed cell volumeUSG: UltrasonographySEAR: Southeast Asian region.

Competing Interests

The authors declare that they have no competing interests.

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Research and TreatmentAIDS

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Gastroenterology Research and Practice

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Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com